Is NPHP1 p.Glu218= (c.654G>A) pathogenic?

NPHP1 p.Glu218= (c.654G>A) is classified Benign in NPHP1 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 58.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with nephronophthisis.

What condition is associated with NPHP1 p.Glu218= (c.654G>A)?

NPHP1 p.Glu218= (c.654G>A) is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPHP1 p.Glu218=

Q: How common is NPHP1 p.Glu218= (c.654G>A) in the general population?

NPHP1 p.Glu218= (c.654G>A) is common (popmax 58.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.654G>A · rs11675767 · VCV92719

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 58.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.9
Overall
CADD	0.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 58.8% East Asian · 26,358/44,794 alleles

Filtering AF 58.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 58%

Overall 35.1% 564,744/1,610,892 alleles · common exomes 506,143/1,458,928 · genomes 58,601/151,964 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	58.8%	2
South Asian	49.8%	2
African / African-American	49.2%	2
Middle Eastern	39.4%	3
Admixed American	37.5%	3
Remaining individualsnot grpmax-eligible	36.1%	3
Amishnot grpmax-eligible	34.7%	3
Ashkenazi Jewishnot grpmax-eligible	33.1%	3
European (non-Finnish)	32.6%	3
Finnishnot grpmax-eligible	22.9%	4

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPHP1
Protein: p.Glu218=
Coding: c.654G>A
MANE Select: NM_001128178
dbSNP: rs11675767
Type: single nucleotide variant
Location: chr2:110165126 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 218: the 'disordered' region

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP1 p.Glu218Lys Uncertain significance ★ ⚠ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nphp1-p-glu218 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown